Program Director/Principal Investigator (Last, First, Middle): Butcher, Eugene C. 1R01 AI082318-01 Our goal for this 2 year award is to define in detail the therapeutic potential of recently identified tolerogenic DC populations in graft versus host disease (GVHD). We have recently identified CCR9- expressing plasmacytoid DCs as an extremely potent tolerogenic subset of DCs. Our initial studies indicate that viable allogeneic CCR9+ pDCs inhibit GVHD in irradiated recipients reconstituted with allogeneic bone marrow and effector CD4+ T cells. Here, tolerogenic pDC requirements for effectiveness and durability of induced allo-specific tolerance in the GVHD model will be characterized in studies examining a) the role of pDC numbers in the context of optimal myeloablative recipient conditioning regimens, b) the ability of fixed or non-proliferative tolerogenic pDCs to suppress GVHD, and c) the role of CCR9 itself in tolerance induction. To test the hypothesis that pDCs are uniquely suited to GVHD treatment, the GVHD-suppressing potential of these highly tolerogenic pDCs will be compared to that of a putative tolerogenic myeloid DC population. Graft vs host responses are deleterious when directed at normal host tissues, but can be beneficial in therapeutic anti-tumor (graft vs tumor or GVT) regimens. Regulatory T cells (Tregs) can control systemic GVHD while allowing GVT activity. To test the hypothesis that CCR9+ pDCs can suppress GVHD without abrogating GVT, experiments will be carried out in a mouse leukemia model. Together, these studies will define in detail the potential of CCR9+ pDCs to suppress deleterious effects of GVHD in settings modeling situations in which human patients encounter pathogenic GVHD responses.